Generation of Lamprey Monoclonal Antibodies (Lampribodies) Using the Phage Display System.

The variable lymphocyte receptors (VLRs) consist of leucine rich repeats (LRRs) and comprise the humoral antibodies produced by lampreys and hagfishes. The diversity of the molecules is generated by stepwise genomic rearrangements of LRR cassettes dispersed throughout the VLRB locus. Previously, target-specific monovalent VLRB antibodies were isolated from sea lamprey larvae after immunization with model antigens. Further, the cloned VLR cDNAs from activated lamprey leukocytes were transfected into human cell lines or yeast to select best binders. Here, we expand on the overall utility of the VLRB technology by introducing it into a filamentous phage display system. We first tested the efficacy of isolating phage into which known VLRB molecules were cloned after a series of dilutions. These experiments showed that targeted VLRB clones could easily be recovered even after extensive dilutions (1 to 109). We further utilized the system to isolate target-specific "lampribodies" from phage display libraries from immunized animals and observed an amplification of binders with relative high affinities by competitive binding. The lampribodies can be individually purified and ostensibly utilized for applications for which conventional monoclonal antibodies are employed

Regolith production and transport at the Susquehanna Shale Hills Critical Zone Observatory, Part 2: Insights from meteoric 10Be

Regolith-mantled hillslopes are ubiquitous features of most temperate landscapes, and their morphology reflects the climatically, biologically, and tectonically mediated interplay between regolith production and downslope transport. Despite intensive research, few studies have quantified both of these mass fluxes in the same field site. Here we present an analysis of 87 meteoric 10Be measurements from regolith and bedrock within the Susquehanna Shale Hills Critical Zone Observatory (SSHO), in central Pennsylvania. Meteoric 10Be concentrations in bulk regolith samples (n=73) decrease with regolith depth. Comparison of hillslope meteoric 10Be inventories with analyses of rock chip samples (n=14) from a 24 m bedrock core confirms that >80% of the total inventory is retained in the regolith. The systematic downslope increase of meteoric 10Be inventories observed at SSHO is consistent with 10Be accumulation in slowly creeping regolith (∼ 0.2 cm yr-1). Regolith flux inferred from meteoric 10Be varies linearly with topographic gradient (determined from high-resolution light detection and ranging-based topography) along the upper portions of hillslopes at SSHO. However, regolith flux appears to depend on the product of gradient and regolith depth where regolith is thick, near the base of hillslopes. Meteoric 10Be inventories at the north and south ridgetops indicate minimum regolith residence times of 10.5 ± 3.7 and 9.1 ± 2.9 ky, respectively, similar to residence times inferred from U-series isotopes in Ma et al. (2013). The combination of our results with U-series-derived regolith production rates implies that regolith production and erosion rates are similar to within a factor of two on SSHO hillcrests. ©2013. American Geophysical Union. All Rights Reserved

Field Study of Abrasive Blasting with Quartz Sand: Factors Affecting the Potential for Incidental Exposure to Respirable Silica

The use of quartz sand in high velocity abrasive blasting of steel is common in many Gulf Coast fabrication facilities. This activity has been recognized as generating high respirable silica concentrations in proximity to the blasting nozzles as evidenced by personal samples taken on blast workers over the years by several investigators. There remains limited published data useful to "plan" a sand blasting site such that other workers, however far away, are not exposed to damaging concentrations of respirable silica. Fixed sampling arrays consisting of personal respirable samplers (ACGIH and BMRC outpoints) and high volume samplers (using 8" x 10") filters were positioned in down-plume positions for 10 different worksites in a large Gulf Coast steel fabrication yard during the month of July 1991. Results of 126 gravimetric respirable samples, 34 high volume samples, 14 "zero dilution" chamber tests, and 42 analyses(contracted) for crystalline quartz demonstrated several interesting results. In general, downwind respirable silica concentrations varied as distance (D[-1.17]) from the source. The results were also consistent with Button's point source model (for the distances studied) where concentration varied as the distance (D[-1.76]) from the source. Source concentrations (0-50'from the blasting) measured by the fixed array averaged 3.61 mg/m[3]) but did not approach the "blast zone" concentrations measured by Samimi, et al— 37.2 mg/m[3]. Short-term sandblasting chamber studies to quantify a "zero dilution" generation rate yielded concentrations 2-3 orders of magnitude higher than the fixed array concentrations. Turbulent "free jet" mixing and sand blasting normal work patterns can explain various concentration magnitudes. Analytical results of crystalline silica analyses were comparable to gravimetric results such that their specification for a field study of sand blasting is not cost effective when the quartz content of the sand blasting sand is known. Using the data collected and the power laws studied it is estimated that 1100-2400 feet from the sandblast site airborne downwind concentrations will reliably dilute below the "action level" of 0.05 mg/m[3] respirable crystalline quartz.Master of Science in Public Healt

Learning to Generate Better Than Your LLM

Reinforcement learning (RL) has emerged as a powerful paradigm for fine-tuning Large Language Models (LLMs) for text generation. In particular, recent LLMs such as ChatGPT and GPT-4 can engage in fluent conversations with users after finetuning with RL. Capitalizing on key properties of text generation, we seek to investigate RL algorithms beyond general purpose algorithms like Proximal Policy Optimization (PPO). In particular, we extend RL algorithms to allow them to interact with a dynamic black-box guide LLM and propose RL with guided feedback (RLGF), a suite of RL algorithms for LLM fine-tuning. We provide two ways for the guide LLM to interact with the LLM to be optimized for maximizing rewards. The guide LLM can generate text which serves as additional starting states for the RL optimization procedure. The guide LLM can also be used to complete the partial sentences generated by the LLM that is being optimized, treating the guide LLM as an expert to imitate and surpass eventually. We experiment on the IMDB positive sentiment, CommonGen, and TL;DR summarization tasks. We show that our RL algorithms achieve higher performance than supervised learning (SL) and the RL baseline PPO, demonstrating the benefit of interaction with the guide LLM. On both CommonGen and TL;DR, we not only outperform our SL baselines but also improve upon PPO across a variety of metrics beyond the one we optimized for. Our code can be found at https://github.com/Cornell-RL/tril.Comment: 23 pages, 5 figures, 7 tables, 4 algorithm

Policy-Gradient Training of Language Models for Ranking

Text retrieval plays a crucial role in incorporating factual knowledge for decision making into language processing pipelines, ranging from chat-based web search to question answering systems. Current state-of-the-art text retrieval models leverage pre-trained large language models (LLMs) to achieve competitive performance, but training LLM-based retrievers via typical contrastive losses requires intricate heuristics, including selecting hard negatives and using additional supervision as learning signals. This reliance on heuristics stems from the fact that the contrastive loss itself is heuristic and does not directly optimize the downstream metrics of decision quality at the end of the processing pipeline. To address this issue, we introduce Neural PG-RANK, a novel training algorithm that learns to rank by instantiating a LLM as a Plackett-Luce ranking policy. Neural PG-RANK provides a principled method for end-to-end training of retrieval models as part of larger decision systems via policy gradient, with little reliance on complex heuristics, and it effectively unifies the training objective with downstream decision-making quality. We conduct extensive experiments on various text retrieval benchmarks. The results demonstrate that when the training objective aligns with the evaluation setup, Neural PG-RANK yields remarkable in-domain performance improvement, with substantial out-of-domain generalization to some critical datasets employed in downstream question answering tasks

Landscape heterogeneity drives contrasting concentration–discharge relationships in shale headwater catchments

Solute concentrations in stream water vary with discharge in patterns that record complex feedbacks between hydrologic and biogeochemical processes. In a comparison of three shale-underlain headwater catchments located in Pennsylvania, USA (the forested Shale Hills Critical Zone Observatory), and Wales, UK (the peatland-dominated Upper Hafren and forest-dominated Upper Hore catchments in the Plynlimon forest), dissimilar concentration–discharge (C–Q) behaviors are best explained by contrasting landscape distributions of soil solution chemistry – especially dissolved organic carbon (DOC) – that have been established by patterns of vegetation and soil organic matter (SOM). Specifically, elements that are concentrated in organic-rich soils due to biotic cycling (Mn, Ca, K) or that form strong complexes with DOC (Fe, Al) are spatially heterogeneous in pore waters because organic matter is heterogeneously distributed across the catchments. These solutes exhibit non-chemostatic behavior in the streams, and solute concentrations either decrease (Shale Hills) or increase (Plynlimon) with increasing discharge. In contrast, solutes that are concentrated in soil minerals and form only weak complexes with DOC (Na, Mg, Si) are spatially homogeneous in pore waters across each catchment. These solutes are chemostatic in that their stream concentrations vary little with stream discharge, likely because these solutes are released quickly from exchange sites in the soils during rainfall events. Furthermore, concentration–discharge relationships of non-chemostatic solutes changed following tree harvest in the Upper Hore catchment in Plynlimon, while no changes were observed for chemostatic solutes, underscoring the role of vegetation in regulating the concentrations of certain elements in the stream. These results indicate that differences in the hydrologic connectivity of organic-rich soils to the stream drive differences in concentration behavior between catchments. As such, in catchments where SOM is dominantly in lowlands (e.g., Shale Hills), we infer that non-chemostatic elements associated with organic matter are released to the stream early during rainfall events, whereas in catchments where SOM is dominantly in uplands (e.g., Plynlimon), these non-chemostatic elements are released later during rainfall events. The distribution of SOM across the landscape is thus a key component for predictive models of solute transport in headwater catchments

Chemical Mixing Study for the Hanford TWRS Supporting Facilities (U)

This Engineering Calculation addresses consequences of mixing any two hazardous chemicals contained in the same section of TWRS supporting facilities, as screened in accordance with `Westinghouse Savannah River Company Engineering and Construction Services Division Guidelines and Methods.

Biotic controls on solute distribution and transport in headwater catchments

Solute concentrations in stream water vary with discharge in patterns that record complex feedbacks between hydrologic and biogeochemical processes. In a comparison of headwater catchments underlain by shale in Pennsylvania, USA (Shale Hills) 5 and Wales, UK (Plynlimon), dissimilar concentration-discharge behaviors are best explained by contrasting landscape distributions of soil solution chemistry – especially dissolved organic carbon (DOC) – that have been established by patterns of vegetation. Specifically, elements that are concentrated in organic-rich soils due to biotic cycling (Mn, Ca, K) or that form strong complexes with DOC (Fe, Al) are spatially heteroge- 10 neous in pore waters because organic matter is heterogeneously distributed across the catchments. These solutes exhibit non-chemostatic “bioactive” behavior in the streams, and solute concentrations either decrease (Shale Hills) or increase (Plynlimon) with increasing discharge. In contrast, solutes that are concentrated in soil minerals and form only weak complexes with DOC (Na, Mg, Si) are spatially homogeneous in pore waters 15 across each catchment. These solutes are chemostatic in that their stream concentrations vary little with stream discharge, likely because these solutes are released quickly from exchange sites in the soils during rainfall events. Differences in the hydrologic connectivity of organic-rich soils to the stream drive differences in concentration behavior between catchments. As such, in catchments where soil organic matter (SOM) is dom- 20 inantly in lowlands (e.g., Shale Hills), bioactive elements are released to the stream early during rainfall events, whereas in catchments where SOM is dominantly in uplands (e.g., Plynlimon), bioactive elements are released later during rainfall events. The distribution of vegetation and SOM across the landscape is thus a key component for predictive models of solute transport in headwater catchments

NF-κB Mediates FGF Signal Regulation of msx-1 Expression

AbstractThe nuclear factor-κB (NF-κB) family of transcription factors is involved in proliferation, differentiation, and apoptosis in a stage- and cell-dependent manner. Recent evidence has shown that NF-κB activity is necessary for both chicken and mouse limb development. We report here that the NF-κB family member c-rel and the homeodomain gene msx-1 have partially overlapping expression patterns in the developing chick limb. In addition, inhibition of NF-κB activity resulted in a decrease in msx-1 mRNA expression. Sequence analysis of the msx-1 promoter revealed three potential κB-binding sites similar to the interferon-γ (IFN-γ) κB-binding site. These sites bound to c-Rel, as shown by electrophoretic mobility shift assay (EMSA). Furthermore, inhibition of NF-κB activity significantly reduced transactivation of the msx-1 promoter in response to FGF-2/-4, known stimulators of msx-1 expression. These results suggest that NF-κB mediates the FGF-2/-4 signal regulation of msx-1 gene expression

Documentation of individualized preoperative risk assessment: a multi-center study

Background: Individual surgical risk assessment (ISRA) enhances patient care experience and outcomes by informing shared decision-making, strengthening the consent process, and supporting clinical management. Neither the use of individual pre-surgical risk assessment tools nor the rate of individual risk assessment documentation is known. The primary endpoint of this study was to determine the rate of physician documented ISRAs, with or without a named ISRA tool, within the records of patients with poor outcomes. Secondary endpoints of this work included the effects of age, sex, race, ASA class, and time and type of surgery on the rate of documented presurgical risk. / Methods: The records of non-obstetric surgical patients within 22 community-based private hospitals in Arizona, Colorado, Nebraska, Nevada, and Wyoming, between January 1 and December 31, 2017, were evaluated. A two-sample proportion test was used to identify the difference between surgical documentation and anesthesiology documentation of risk. Logistic regression was used to analyze both individual and group effects associated with secondary endpoints. / Results: Seven hundred fifty-six of 140,756 inpatient charts met inclusion criteria (0.54%, 95% CI 0.50 to 0.58%). ISRAs were documented by 16.08% of surgeons and 4.76% of anesthesiologists (p < 0.0001, 95% CI −0.002 to 0.228). Cardiac surgeons documented ISRAs more frequently than non-cardiac surgeons (25.87% vs 16.15%) [p = 0.0086, R-squared = 0.970%]. Elective surgical patients were more likely than emergency surgical patients (19.57 vs 12.03%) to have risk documented (p = 0.023, R-squared = 0.730%). Patients over the age of 65 were more likely than patients under the age of 65 to have ISRA documentation (20.31 vs 14.61%) [p = 0.043, R-squared = 0.580%]. Only 10 of 756 (1.3%) records included documentation of a named ISRA tool. / Conclusions: The observed rate of documented ISRA in our sample was extremely low. Surgeons were more likely than anesthesiologists to document ISRA. As these individualized risk assessment discussions form the bedrock of perioperative informed consent, the rate and quality of risk documentation must be improved